Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

Non human studies

The available data on low benzene naphtha stream 68476-55-1 and on the specific component toluene do not reveal any reproductive toxicity of a severity that would warrant classification.

In a combined repeated dose toxicity/reproduction/developmental toxicity study, rats were exposed to CAS 68476 -55 -1 by whole body inhalation exposure at concentrations of 0, 100, 300 or 1000 ppm, 6 h/day for 7 days/week. Groups of 12 male and female rats were exposed for a 2-week pre-mating period and throughout mating. Females were then exposed until Day 19 of gestation. The females were allowed to litter and rear their offspring to Day 4 of lactation. Records of clinical condition, bodyweight, food consumption, oestrous cycles, mating performance, litter data, organ weights and macroscopic pathology were undertaken. There was no evidence of any reproduction developmental toxicity. The oestrous cycle was unaffected by exposure, and mating performance, fertility indices and gestation length were similar in all groups.

Two key studies are identified for toluene.

Roberts et al (2003) conducted a combined two-generation fertility and teratogenicity inhalation study in rats. Exposure to toluene was at 0, 100, 500 or 2000 ppm 6 h/day, 7 days/week during an 80 day pre-mating period and 15 day mating period. Females were further exposed during gestation (GD 1-20) and lactation (LD 5-21). Toluene exposure did not induce adverse effects on fertility and the NOAEC for effects on fertility was 2000 ppm (7500 mg/m3), the highest dose tested.

In the study of Ono et al rats were exposed to toluene vapour at 600 and 2000 ppm for 6 h/day, and effects on their fertility were investigated. Females were exposed from 14 days before mating until day 7 of gestation. Males were exposed for a total of 90 days, including the mating period; treatment was begun 60 days before pairing, and toxicity with respect to testicular and reproductive functions was examined. Although no abnormalities were seen in mating behaviour or fertility in the males exposed to 2000 ppm decreases in the weights of the epididymides and sperm count were observed. The NOAEC for effects on male fertility was 600 ppm (2261 mg/m3).

Human information

There are no human data for low benzene naphtha streams.

For toluene the EU RAR (2003) concluded “In humans, no studies of effects of toluene on sperm count were found. Limited data in humans have not shown indication of effects on fertility in men or menstrual function in women”. Consequently a value of 2261 mg/m3 from the Ono study will be taken into consideration for classification.

References

EU RAR (2003). Toluene risk assessment report. European Union Risk Assessment Report, Volume 30.

Ono A, Sekita K, Ogawa Y, Hirose A, Suzuki S, Saito M, Naito K, Kaneko T, Furuya T, Kawashima K, Yasuhara K, Matsumoto K, Tanaka S, Inoue T and Kurokawa Y (1996). Reproductive and developmental toxicity studies of toluene II. Effects of inhalation exposure on fertility in rats. Journal of Environmental Pathology Toxicology and Oncology 15, 9-20.

Roberts LG, Bevans AC and Schreiner CA (2003). Developmental and reproductive toxicity evaluation of toluene vapor in the rat. 1. Reproductive toxicity. Reproductive Toxicology, 17, 649-658. Testing laboratory: International Research and Development Corporation, Mattawan, MI, USA.


Short description of key information:
It is recognised that there is a data gap for a multi-generation study (REACH reference 8.7.3). The applicant submits that this study does not need to be conducted since data are available on a low benzene naphtha stream, CAS 68476-55-1 and the component substance, toluene, which are adequate for the purposes of classification and labelling and/or risk assessment of the UVCB substances included in this category.
There is a 4 week general toxicity and reproduction/developmental toxicity screening studies (OECD 422) with CAS 68476-55-1, a low benzene naphtha stream by the inhalation route. There was no evidence of effects on reproduction or fertility at the highest concentration tested (1012 ppm). Toluene is not classified for effects on fertility.

Effects on developmental toxicity

Description of key information
It is recognised that there is a data gap for a developmental toxicity study (REACH reference 8.7.2). The applicant submits that this study does not need to be conducted since data are available on component substances which are adequate for the purposes of classification and labelling and/or risk assessment of the UVCB substances included in this category. There is a 4 week general toxicity and reproduction/developmental toxicity screening studies (OECD 422) with a low benzene naphtha stream.  In rats exposed by inhalation study to CAS 68476-55-1, there was no evidence of effects on pup development at an atmosphere concentration of 1012 ppm. For the specific component toluene there is some evidence of developmental toxicity (lower body weight at birth and delayed vaginal opening) at exposure concentrations ≥ 1000 ppm, concentrations which are associated with slight maternal toxicity. The NOAEC for developmental and maternal effects is 600 ppm (2261 mg/m3). Therefore for streams that contain toluene at concentrations greater than or equal to 5% (EU/DPD) or 3 (GHS/CLP), classification is required for developmental toxicity. 
Additional information

Non-human information

Groups of 12 female rats were exposed for a 2-week pre-mating period, throughout mating and until Day 19 of gestation to CAS 68476-55-1 by whole body inhalation exposure at concentrations of 0, 100, 300 or 1000 ppm, 6 h/day. The females were allowed to litter and rear their offspring to Day 4 of lactation. Maternal bodyweight, clinical signs and food consumption were recorded and litter assessments included litter size, offspring survival and clinical condition, sex ratio, pup body weight and pup body weight gain. There was no evidence of developmental toxicity. There were no adverse effects upon survival or growth of the offspring in uterus or up to Day 4 of lactation. The NOAEC for developmental toxicity of CAS 68476-55-1 was 1000 ppm.

 

Toluene (Classification: EU – Harmful Xn, R63; GHS/CLP – Category 2, H361d): There is no evidence that toluene produces malformation in animals or humans. There is some evidence of developmental toxicity (lower body weight at birth and delayed vaginal opening) at toluene exposure concentrations ≥ 1000 ppm, concentrations which are associated with slight maternal toxicity. The NOAEC for developmental and maternal effects is 600 ppm (2261 mg/m3) (Thiel and Chahoud, 1997).

Justification for classification or non-classification

There are sufficient data available on a low benzene naphtha stream and the component substance, toluene, to conclude that streams within this category that contain less than 5% (EU/DSD) or 3% (GHS/CLP) toluene are not reproductive toxicants and do not require a label for this endpoint.

On the basis of possible effects on development in animals studies with toluene, low benzene naphtha streams which contain ≥ 3% toluene should be classified Category 2, H361d according to GHS/CLP In addition, low benzene naphtha streams that contain ≥ 5% toluene are classified as follows: Xn, R63, according to Dir 67/548.